This application is for a KO5 Award from NIDA. Since joining the faculty in 1987, my laboratory has made significant contributions to an improved understanding of the molecular mechanisms underlying drug addiction. I have been supported for the past 5 years by a NIDA KO2 Award, which played an important role in my career development by reducing my clinical, teaching, and administrative duties. The requested K05 Award would make it possible for me to maintain this focus on academic pursuits and thereby further advance my research and educational activities. The proposed program of research involves two areas of study: 1) the role of cAMP pathway in mediating some of the long-term actions of opiates in the locus coeruleus, and 2) the role of a series of common, biochemical adaptations in mediating some of the long-term actions of cocaine and opiates in the mesolimbic dopamine system. Support from this K05 Award will enable me to focus on several technical advances that will greatly facilitate the ability of relating specific molecular adaptations (caused by chronic drug exposure in one of these discrete brain regions) to specific aspects of behavioral plasticity to drugs of abuse. These will include the further development of two molecular approaches, which by avoiding developmental consequences of genetic mutations and restricting them to specific brain regions, avoid limitations currently encountered with traditional transgenic and knockout mice: . Use of viral-mediated gene transfer to over-express specific proteins of interest in highly restricted populations of neurons in adult rats. . Use of inducible, targeted transgenic or knockout mice, in which a gene of interest can be turned on or off, in a discrete region of brain, at any point in the adult life of the animal. This also will include further development of behavioral models of drug abuse and addiction, which will be coupled with the molecular approaches. These experimental approaches, made possible by a K05 Award, promise to reveal new insight into the mechanisms by which repeated drug exposure leads to the behavioral plasticity of drug addiction.